3/02/2005 @ 6:00AM

The Virus That Took Down Tysabri

The multiple sclerosis drug Tysabri might have squashed competition from some of the world’s biotech giants, but in the end it was pushed off the market by a virus smaller than the tiniest transistors on any computer chip.

Drugmakers
Biogen Idec
and
Elan
pulled Tysabri off the market because of two suspected cases of progressive multifocal leukoencephalopathy, or PML, a brain-wasting disease caused by the JC virus that can cause paralysis, blindness, dementia or death. The disease normally occurs only in patients with compromised immune systems. But it’s possible that Tysabri made patients susceptible to PML by changing the way certain white blood cells function. This week, Biogen and Elan will meet with experts on the JC virus in the hopes that they can settle the issue.

The JC virus, discovered in 1971 and named with the initials of the patient in whom it was found, is present in almost everyone but only destroys the brain when something damages the immune system and allows the virus to run rampant. “You’re already infected,” says
Igor
Koralnik
Igor Koralnik
, director of the HIV Neurology Center at Harvard’s Beth-Israel Deaconess Medical Center.

Koralnik entered medical school in the 1980s, just in time for the AIDS epidemic to cause sudden outbreaks of PML. Since the first description of the disease in 1958, it had remained a rare occurrence, seen mostly in organ transplant patients whose immune systems were suppressed by drugs. But AIDS destroys the white blood cells that normally halt the JC virus in its tracks.

About 5% of people with full-blown AIDS develop PML. When Koralnik first started treating the disease, it was almost always fatal. Now, at a time when highly powerful antiretroviral drugs such as those made by
Pfizer
,
Bristol-Myers Squibb
and
Gilead
keep the HIV virus at bay, PML still kills half the time. Most of those who survive are left with paralysis, dementia, blindness or the inability to speak.

In 1990, Koralnik published an article in The New England Journal of Medicine about brain ailments that afflict AIDS patients. Among them, PML was the most untreatable. AIDS doctors, he found, knew too little about neurology to treat it, and HIV doctors knew little of brain disorders. “I thought I could make a difference,” Koralnik says. Since then, he has been working to try to find therapies that could fight the disease, and to create a simian version of the virus that could be used to study it in monkeys.

The reason the virus becomes so damaging once the immune system can no longer keep it in check is that it infects brain cells that are charged with creating a protective lining for neurons, much like the rubber coating on copper wires. Without that lining, the circuitry of the brain is left disabled. This destructive process, called demyelination, is essentially what happens in MS–except in PML, it is much more rapid.

The irony here is that the same white cells that are killed by the AIDS virus, called T-cells, are the cause of MS. Defective T-cells strip the lining from nerves in the brain much as the JC virus does, although the process is much slower. Tysabri works by altering the behavior of the T-cells, hampering their movement into the brain.

It’s possible this allows the JC virus to come out of check in patients treated with the drug. But the patients who developed PML while on Tysabri were also receiving Avonex, another Biogen MS drug. Steroids, another treatment, might also have suppressed the immune system.

“It’s much too early to tell if it’s the Tysabri, or the dual therapy, or the patients were on steroids,” Koralnik says. He will meet with Biogen and Elan on Friday.

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